Amyloidogenic sequences in native protein structures - PubMed (original) (raw)

Amyloidogenic sequences in native protein structures

Susan Tzotzos et al. Protein Sci. 2010 Feb.

Abstract

Numerous short peptides have been shown to form beta-sheet amyloid aggregates in vitro. Proteins that contain such sequences are likely to be problematic for a cell, due to their potential to aggregate into toxic structures. We investigated the structures of 30 proteins containing 45 sequences known to form amyloid, to see how the proteins cope with the presence of these potentially toxic sequences, studying secondary structure, hydrogen-bonding, solvent accessible surface area and hydrophobicity. We identified two mechanisms by which proteins avoid aggregation: Firstly, amyloidogenic sequences are often found within helices, despite their inherent preference to form beta structure. Helices may offer a selective advantage, since in order to form amyloid the sequence will presumably have to first unfold and then refold into a beta structure. Secondly, amyloidogenic sequences that are found in beta structure are usually buried within the protein. Surface exposed amyloidogenic sequences are not tolerated in strands, presumably because they lead to protein aggregation via assembly of the amyloidogenic regions. The use of alpha-helices, where amyloidogenic sequences are forced into helix, despite their intrinsic preference for beta structure, is thus a widespread mechanism to avoid protein aggregation.

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Figures

Figure 1

Figure 1

Selection of amyloidogenic proteins in native conformation with amyloidogenic sequences highlighted (amyloidogenic residue numbers in parentheses for given protein model refer to residues considered amyloidogenic for calculations in present study). Biological molecules are illustrated unless otherwise indicated. a) β-lactoglobulin, PDB ID 1BEB (Asp11-Tyr20, Lys101-Ser110, Ser116-Pro126, His146-Asn152), b) prolactin, PDB ID 1RW5 (Gly7-Ser34, Arg43-Ser57), c) repA pPS10 Pseudomonas, PDB ID 1HKQ (Leu26-Ile34), d) B. subtilis ‘YjcG’ protein, PDB ID 2D4G (Leu151-Asn156). Images were created using PyMol (www.pymol.org).

Figure 2

Figure 2

(a) Correlation between relative accessible surface area (ASA) per residue and strand content in amyloidogenic sequences of 30 native proteins (one average value per protein). Correlation coefficient = −0.4568, p = 0.0112; slope of trendline = −0.1896. (b) Correlation between relative accessible surface area (ASA) per residue and strand content in S-set of amyloidogenic sequences. Correlation coefficient = −0.5239, p = 0.0123; slope of the trendline = −0.2804. (c) Correlation between relative accessible surface area (ASA) per residue and strand content in non-amyloidogenic sequences of 30 native proteins. Correlation coefficient = −0.4735, p = 0.0082; slope of the trendline = −0.2906.

Figure 3

Figure 3

(a) Correlation between relative accessible surface area (ASA) per residue and helical content in amyloidogenic sequences of 30 native proteins (one average value per protein). Correlation coefficient = 0.4244, p = 0.0194; slope of trendline = 0.1744. (b) Correlation between relative accessible surface area (ASA) per residue and helical content in H-set of amyloidogenic sequences. Correlation coefficient = 0.0610, p = 0.7823; slope of the trendline = −0.0351. (c) Correlation between relative accessible surface area (ASA) per residue and helical content in non-amyloidogenic sequences of 30 native proteins. Correlation coefficient = 0.2414, p = 0.1987; slope of the trendline = 0.1384.

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